Copyright: Dennis Kunkel Microscopy, Inc. (www.denniskunkel.com). Microscopic view of Methicillin-resistant Staphylococcus aureus (MRSA)
Motivation and Background
Infectious diseases are the second leading cause of death worldwide and the third leading cause of death in developed countries [2]. Metihcillin-resistant Staphylococcus aureus (MRSA) remains one of the principal resistant bacterial pathogens causing serious healthcare-associated and community-onset infections. About one-third of people in the world have S. aureus bacteria on their bodies at any given time, primarily in the nose and on the skin and can be present without causing an active infection [2]. MRSA is characterized by causing complicated skin and skin-structure infections such as boils, scalded- skin syndrom, and impetigo along with serious hospital-acquired infections, especially bloodstream infections and ventilator-associated pneumonia [1,4]. The globally pervasive drug-resistant pathogen, Staphylococcus aureus (S. aureus), has increased the proportion of MRSA related infections in hospital intensive care units from just 2 percent in 1974 to 64 percent in 2004 [2]. Overall, MRSA is estimated to cause 171 200 healthcare-associated infections (HAIs) in Europe each year, corresponding to 44% of all HAIs [1]. It is also estimated to cause 5400 attributable extra deaths and over a million extra days of hospitalization associated with theses infections [1]. Moreover, accumulating data indicates that MRSA infections are associated with a worse prognosis than meticillin-susceptible S. aureus (MSSA) infections [1]. Its presence in the community has been rising similarly, posing a significant public health burden. Therefore, the continued emergence of resistant strains of bacteria such as MRSA demands an urgent revival of the search for new antibiotics.
Target Information
S. aureus has developed numerous mechanisms of virulence and strategies to evade the human immune system, including a host of surface proteins, secreted enzymes, and toxins [2]. In order to initiate infection, S. aureus must first adhere to host tissues or prosthetic devices [2]. To accomplish this, S. aureususes uses a constellation of surface proteins known as microbial surface components that recognize adhesive matrix molecules (MSCRAMMS) [1,2]. Each strain of S. aureus has its own genetic stock of MSCRAMMS and thus yields to a strain-specific adhesion preference and concomitant infection pattern. Once affixed to a surface, S. aureus capitatlizes on various resources to evade the host immune system in order to yield sufficient time for an infection to take hold [1,4]. This is where the mechanism formation of biofilms takes place, surface-associated bacterial collections situated within self-made extracellular polymeric matrices that allow microbial communities protection against host defenses and antibiotics [2]. In addition, research shows that S. aureus uses bacterial fibronectin-binding proteins, a type of MSCRAMM, to evade host immune cell phagocytosis [1,2]. Also, to further avoid antibody-mediated immunity, S. aureus utilizes an additional surface protein virulence factor called Protein A [1]. In binding to the universal Fc region of host immunoglobulins, Protein A inhibits opsonization and phagocytosis [1,2].
Schematic diagram of S. aureus depicting basic structure and a selection of virulence factors
Drug Information
The Centers for Disease Control (CDC) estimates that roughly two million people in the United States will develop bacterial infections while in the hospital and that nearly 90, 000 will die from associated complications. Close to 70 percent of the bacteria responsible for these infections will be resistant to at least one commonly used antibiotic [2]. Antibiotic resistant organisms continue to spread at alarming rates and pose a serious public health concern.
Typically, healthcare providers can treat many S. aureus skin infections by draining the abscess or boil and may not need to use antibiotics. Such is the case for mild to moderate skin infections where incision and drainage is the first-line treatment by a healthcare provider. However, for severe infection doctors will typically use vancomycin intravenously and will void treating the patient with beta-lactam antibiotics, a class of antibiotic observed not to be effective in killing the staph bacteria [1]. The bactericidal action of vancomycin results primarily from inhibition of cell-wall biosynthesis [3]. In addition, vancomycin alters bacterial-cell membrane permeability and RNA synthesis and there is no cross-resistance between vancomycin and other antibiotics [3].
The formula for Vancomycin is C66H75Cl2N9O24, molecular weight at 1449.2536 g/mol, and CAS number 1404-90-6 [4]. The delivery method for Vancomycin can either be in capsules or injection and can range in side effects such as back pain, gas, headache, nausea, stomach pain, tiredness, and vomiting [3]. However, seek medical attention right away if any of the severe side effects occur when using Vancomycin capsules: severe allergic reactions, chest pain, difficult or painful urination, fainting, fever, chills, sore throat, flushing, red or blistered skin, severe or persistent diarrhea, dizziness, shortness of breath, swelling of the hands, ankles or feet, unusual bruising etc. [3]. In addition, manufacturing for Vancomycin includes Hospira, Inc. [3].
Even though vancomycin has been used for patients with sever infection, Tetraphase Pharmaceutical, a company based on specifically this research, has already developed a cadre of drug candidates with the potential to treat a wide range of infectious diseases. Moreover, there is a leading drug candidate called TP-434 in which has shown a great preclinical promise as a potent antibacterial against a broad spectrum of susceptible and multidrug-resistant organisms [2]. Therefore, as the impending crisis continues to worsen over the past decade, academic and biotechnology companies need to continue to search and discover for new antibiotics on the account of the continued emergence of resistance strains of bacteria such as MRSA in which demands an urgent revival [2]. After all, MRSA itself is only a symptom of a broader phenomenon, a harbinger of a growing pool of resistant pathogens found both in hospitals and in the community. An efficient, comprehensive, multidisciplinary search for new antibiotics must commence to prepare us to squelch strains of resistant pathogens as they inevitably strike [2,4].
Chemical Structure of Vancomycin
References
[1]Gould, I. M.; David, M. Z.; Esposito, S.; Garau, J.; Lina, G.; Mazzei, T.; Peters, G., New insights into meticillin-resistant Staphylococcus aureus (MRSA) pathogenesis, treatment and resistance. Int J Antimicrob Agents 2012, 39 (2), 96-104.
[2]Morell, E. A.; Balkin, D. M., Methicillin-resistant Staphylococcus aureus: a pervasive pathogen highlights the need for new antimicrobial development. Yale J Biol Med 2010, 83 (4), 223-33.
[4]National Institute of Allergy and Infectious Diseases. Antimicrobial (Drug) Resistance: Methicillin-Resistant Staphylococcus aureus (MRSA). http://www.niaid.nih.gov/topics/ antimicrobialResistance/Examples/mrsa/Pages/default.aspx. (accessed Feb 7, 2012).
Disease/Drug of Interest
Methicillin-resistant Staphylococcus aureus (MRSA), VancomycinCopyright: Dennis Kunkel Microscopy, Inc. (www.denniskunkel.com).
Microscopic view of Methicillin-resistant Staphylococcus aureus (MRSA)
Motivation and Background
Infectious diseases are the second leading cause of death worldwide and the third leading cause of death in developed countries [2]. Metihcillin-resistant Staphylococcus aureus (MRSA) remains one of the principal resistant bacterial pathogens causing serious healthcare-associated and community-onset infections. About one-third of people in the world have S. aureus bacteria on their bodies at any given time, primarily in the nose and on the skin and can be present without causing an active infection [2]. MRSA is characterized by causing complicated skin and skin-structure infections such as boils, scalded- skin syndrom, and impetigo along with serious hospital-acquired infections, especially bloodstream infections and ventilator-associated pneumonia [1,4]. The globally pervasive drug-resistant pathogen, Staphylococcus aureus (S. aureus), has increased the proportion of MRSA related infections in hospital intensive care units from just 2 percent in 1974 to 64 percent in 2004 [2]. Overall, MRSA is estimated to cause 171 200 healthcare-associated infections (HAIs) in Europe each year, corresponding to 44% of all HAIs [1]. It is also estimated to cause 5400 attributable extra deaths and over a million extra days of hospitalization associated with theses infections [1]. Moreover, accumulating data indicates that MRSA infections are associated with a worse prognosis than meticillin-susceptible S. aureus (MSSA) infections [1]. Its presence in the community has been rising similarly, posing a significant public health burden. Therefore, the continued emergence of resistant strains of bacteria such as MRSA demands an urgent revival of the search for new antibiotics.Target Information
S. aureus has developed numerous mechanisms of virulence and strategies to evade the human immune system, including a host of surface proteins, secreted enzymes, and toxins [2]. In order to initiate infection, S. aureus must first adhere to host tissues or prosthetic devices [2]. To accomplish this, S. aureususes uses a constellation of surface proteins known as microbial surface components that recognize adhesive matrix molecules (MSCRAMMS) [1,2]. Each strain of S. aureus has its own genetic stock of MSCRAMMS and thus yields to a strain-specific adhesion preference and concomitant infection pattern. Once affixed to a surface, S. aureus capitatlizes on various resources to evade the host immune system in order to yield sufficient time for an infection to take hold [1,4]. This is where the mechanism formation of biofilms takes place, surface-associated bacterial collections situated within self-made extracellular polymeric matrices that allow microbial communities protection against host defenses and antibiotics [2]. In addition, research shows that S. aureus uses bacterial fibronectin-binding proteins, a type of MSCRAMM, to evade host immune cell phagocytosis [1,2]. Also, to further avoid antibody-mediated immunity, S. aureus utilizes an additional surface protein virulence factor called Protein A [1]. In binding to the universal Fc region of host immunoglobulins, Protein A inhibits opsonization and phagocytosis [1,2].Schematic diagram of S. aureus depicting basic structure and a selection of virulence factors
Drug Information
The Centers for Disease Control (CDC) estimates that roughly two million people in the United States will develop bacterial infections while in the hospital and that nearly 90, 000 will die from associated complications. Close to 70 percent of the bacteria responsible for these infections will be resistant to at least one commonly used antibiotic [2]. Antibiotic resistant organisms continue to spread at alarming rates and pose a serious public health concern.Typically, healthcare providers can treat many S. aureus skin infections by draining the abscess or boil and may not need to use antibiotics. Such is the case for mild to moderate skin infections where incision and drainage is the first-line treatment by a healthcare provider. However, for severe infection doctors will typically use vancomycin intravenously and will void treating the patient with beta-lactam antibiotics, a class of antibiotic observed not to be effective in killing the staph bacteria [1]. The bactericidal action of vancomycin results primarily from inhibition of cell-wall biosynthesis [3]. In addition, vancomycin alters bacterial-cell membrane permeability and RNA synthesis and there is no cross-resistance between vancomycin and other antibiotics [3].
The formula for Vancomycin is C66H75Cl2N9O24, molecular weight at 1449.2536 g/mol, and CAS number 1404-90-6 [4]. The delivery method for Vancomycin can either be in capsules or injection and can range in side effects such as back pain, gas, headache, nausea, stomach pain, tiredness, and vomiting [3]. However, seek medical attention right away if any of the severe side effects occur when using Vancomycin capsules: severe allergic reactions, chest pain, difficult or painful urination, fainting, fever, chills, sore throat, flushing, red or blistered skin, severe or persistent diarrhea, dizziness, shortness of breath, swelling of the hands, ankles or feet, unusual bruising etc. [3]. In addition, manufacturing for Vancomycin includes Hospira, Inc. [3].
Even though vancomycin has been used for patients with sever infection, Tetraphase Pharmaceutical, a company based on specifically this research, has already developed a cadre of drug candidates with the potential to treat a wide range of infectious diseases. Moreover, there is a leading drug candidate called TP-434 in which has shown a great preclinical promise as a potent antibacterial against a broad spectrum of susceptible and multidrug-resistant organisms [2]. Therefore, as the impending crisis continues to worsen over the past decade, academic and biotechnology companies need to continue to search and discover for new antibiotics on the account of the continued emergence of resistance strains of bacteria such as MRSA in which demands an urgent revival [2]. After all, MRSA itself is only a symptom of a broader phenomenon, a harbinger of a growing pool of resistant pathogens found both in hospitals and in the community. An efficient, comprehensive, multidisciplinary search for new antibiotics must commence to prepare us to squelch strains of resistant pathogens as they inevitably strike [2,4].
Chemical Structure of Vancomycin
References
[1]Gould, I. M.; David, M. Z.; Esposito, S.; Garau, J.; Lina, G.; Mazzei, T.; Peters, G., New insights into meticillin-resistant Staphylococcus aureus (MRSA) pathogenesis, treatment and resistance. Int J Antimicrob Agents 2012, 39 (2), 96-104.[2]Morell, E. A.; Balkin, D. M., Methicillin-resistant Staphylococcus aureus: a pervasive pathogen highlights the need for new antimicrobial development. Yale J Biol Med 2010, 83 (4), 223-33.
[3]National Center for Biotechnology Information. PubChem Compound: Vancomycin- Compound Summary. http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=14969&loc=ec_rcs. (accessed Feb 7, 2012).
[4]National Institute of Allergy and Infectious Diseases. Antimicrobial (Drug) Resistance: Methicillin-Resistant Staphylococcus aureus (MRSA). http://www.niaid.nih.gov/topics/ antimicrobialResistance/Examples/mrsa/Pages/default.aspx. (accessed Feb 7, 2012).
External Links
http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=14969&loc=ec_rcs